The discovery of TRIM5 as a factor determining cross-species restriction of the human immunodeficiency virus (HIV) has prompted considerable interest in the TRIM family of E3 ligases that includes other antiviral proteins such as TRIM19, TRIM22, TRIM25 and TRIM28. Given that many members of the TRIM family of proteins are up-regulated in response to interferons, we decided to systematically test their anti-retroviral activities. Combining an expression screen with targeted RNAi experiments, we identified ~20 TRIM proteins that exhibit complex antiviral activities (Uchil et al., 2008). We hypothesize that some of the observed antiviral activities are due to general roles of TRIM proteins in innate immunity. Expression of proteins such as TRIM25 triggers innate immunity signaling cascades that lead to the establishment of an antiviral state. To identify novel TRIM proteins similarly involved in innate immunity, we screened all 55 proteins for their ability to activate or negatively regulate NFkB, AP-1 and type I interferon signaling pathways. Our work identified a number of additional positive regulators of the inflammatory and innate immunity effector protein NFkB. Here we propose to study one of these proteins that appears to play an important role in toll-like receptor (TLR) signaling. Specifically, we will test its potential role in TLR4 signaling, including in mice lacking the protein and initiate the investigation of the molecular mechanism by which this protein regulates innate immunity. Determining the cellular function of this novel TRIM protein is a prerequisite to understand how it manifests its antiviral properties. PUBLIC HEALTH RELEVANCE: Previously, we identified 20 TRIM E3 ligases proteins with complex antiviral proteins. Here we propose to study the potential role of one of these proteins in innate immunity signaling. Determining its cellular function is a prerequisite to understand how it manifests its antiviral properties.